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Updated: Nov 11, 2025
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal
O McMahon1,2, T M Hallam1,2, S Patel3
1Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Insights
The C9 P167S variant, linked to age-related macular degeneration (AMD), shows increased polymerization and function. This finding supports gene therapy targeting the complement system
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss.
- Genetic variants in complement pathways are strongly associated with AMD.
- A rare variant in complement component 9 (C9) P167S is linked to increased AMD risk.
Purpose of the Study:
- To assess the functional consequences of the C9 P167S variant in age-related macular degeneration (AMD).
- To investigate the association between the C9 P167S variant and C9 plasma levels and sC5b-9 in AMD patients.
Main Methods:
- C9 levels were measured in two independent cohorts of AMD patients.
- Electron microscopy was used to analyze membrane attack complex (MAC) structures.
- Functional assays assessed the polymerization and hemolytic activity of the C9 P167S variant.
Main Results:
- The C9 P167S variant was associated with low C9 plasma levels in both cohorts.
- Patients with advanced AMD had elevated sC5b-9, but this was not linked to the P167S polymorphism.
- The P167S variant showed increased polymerization and enhanced hemolytic activity.
Conclusions:
- The C9 P167S AMD risk polymorphism exhibits increased polymerization and functional activity.
- These findings provide a rationale for ongoing gene therapy trials targeting the terminal complement pathway in AMD.
Abstract:
Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.
